Unlike other tissue which can survive extended periods of hypoxia, brain tissue is particularly sensitive to deprivation of oxygen or energy. Permanent damage to neurons can occur during brief periods of hypoxia, anoxia or ischemia. Neurotoxic injury is known to be caused or accelerated by certain excitatory amino acids (EAA) found naturally in the central nervous system (CNS). Glutamate (Glu) is an endogenous amino acid which was early characterized as a fast excitatory transmitter in the mammalian brain. Glutamate is also known as a powerful neurotoxin capable of killing CNS neurons under certain pathological conditions which accompany stroke and cardiac arrest. Normal glutamate concentrations are maintained within brain tissue by energy-consuming transport systems. Under low energy conditions which occur during periods of hypoglycemia, hypoxia or ischemia, cells can release glutamate. Under such low energy conditions the cell is not able to take glutamate back into the cell. Initial glutamate release stimulates further release of glutamate which results in an extracellular glutamate accumulation and a cascade of neurotoxic injury.
It has been shown that the sensitivity of central neurons to hypoxia and ischemia can be reduced by either interfering with synaptic transmission through blockade of the sodium or calcium ion channel or by the specific antagonism of postsynaptic glutamate receptors [see S. M. Rothman and J. W. Olney, "Glutamate and the Pathophysiology of Hypoxia - Ischemic Brain Damage," Annals of Neurology, Vol. 19, No. 2 (1986)]. Glutamate is characterized as a broad spectrum agonist having activity at three neuronal excitatory amino acid receptor sites. These receptor sites are named after the amino acids which selectively excite them, namely: Kainate (KA), N-methyl-D-aspartate (NMDA or NMA) and quisqualate (QUIS). Glutamate is believed to be a mixed agonist capable of binding to and exciting all three receptor types.
Neurons which have EAA receptors on their dendritic or somal surfaces undergo acute excitotoxic degeneration when these receptors are excessively activated by glutamate. Thus, agents which selectively block or antagonize the action of glutamate at the EAA synaptic receptors of central neurons can prevent neurotoxic injury associated with anoxia, hypoxia or ischemia caused by stroke, cardiac arrest or perinatal asphyxia.
Phencyclidine (PCP) and the PCP-like compound ketamine have been found to reduce selectively the excitatory effects of NMDA as compared to KA and QUIS [Anis, N. A. et al, "The Dissociative Anaesthetics, Ketamine and Phencyclidine, Selectively Reduce Excitation of Central Mammalian Neurones by N-Methyl-Aspartate", Br. J. Pharmacol., 79, 565 (1983)]. Other compounds having PCP-like properties such as cyclazocine, kynurenate and various barbiturates such as secobarbital, amobarbital and pentobarbital, have been tested as antagonists in blocking NMDA- or KA-induced neurotoxicity [J. W. Olney et al., "The Anti-Excitotoxic Effects of Certain Anesthetics, Analgesics and Sedative-Hypnotics," Neuroscience Letters, 68, 29-34 (1986)].
A correlation has been found between the PCP binding effects of some PCP-derivative stereoisomers and NMDA antagonism. For example, the stereoselective effects of cis-N-(1-phenyl-4-methylcyclohexyl)piperidine and (+)-1-(1-phenylcyclohexyl)-3-methylpiperidine [(+)-PCMP] over each of their corresponding isomer counterparts in reducing the excitatory action of NMDA have been confirmed in binding and behavioral data [S. D. Berry et al, "Stereoselective Effects of Two Phencyclidine Derivatives on N-Methylaspartate Excitation of Spinal Neurones in the Cat and Rat", Eur. J. Pharm., 96, 261-267 (1983)]. Also, the compound (+)-PCMP has been found to be a potent inhibitor of the specific binding of [.sup.3 H]PCP to rat cerebral cortical membranes [M. E. Goldman et al, "Differentiation of [.sup.3 H]Phencyclidine and (+)-[.sup.3 H]SKF-10,047 Binding Sites in Rat Cerebral Cortex", FEBS Lett., 170, 333-336 (1985)].
Other neurochemical mechanisms by which PCP alters behavior are known. For example, binding assays of the PCP/sigma site have been used to evaluate arylcycloalkylamines [R. Quirion, "Phencyclidine (Angel Dust)/Sigma `Opiate` Receptor: Visualization by Tritium-Sensitive Film", Proc. Natl. Acad. Sci. U.S.A., 78, 5881 (1981)]. PCP-like drugs may induce ipsilateral turning in rats by action on the PCP/sigma receptor as indicated by studies with arylcycloalkylamines, sigma-agonist benzomorphans and 1,3-dioxolanes.
These PCP-like classes of compounds have been found to inhibit NMDA-induced acetylcholine (ACh) release and such ACh release has been correlated with their affinity for the PCP receptor and with behavioral activity [L. D. Snell et al, "Antagonism of N-Methyl-D-Aspartate-Induced Transmitter Release in the Rat Striatum by Phencyclidine-Like Drugs and its Relationship to Turning Behavior", J. Pharmacol.Exp. Ther., 235, No. 1, 50-56 (1985)].
U.S. Pat. No. 4,598,153 to Rice et al. describes a class of compounds, characterized as the "metaphit" family of compounds, which are useful to block receptors of phencyclidine and PCP-like compounds such as ketamine, thereby antagonizing the in vitro effects of PCP and PCP-like compounds. These "metaphit" compounds are shown in particular as acylating agents of the [.sup.3 H]-phencyclidine binding site. Included in the "metaphit" family of compounds are the following:
1-[1-(3-isothiocyanatophenyl)cyclohexyl]piperidine; PA0 1-[1-(2-(4-isothiocyanato)thienyl)cyclohexyl]piperidine; PA0 N-[1-(m-isothiocyanatophenyl)cyclohexyl]ethylamine; PA0 N-[1-(m-(.alpha.-bromoacetylamino)phenyl)cyclohexyl]ethylamine; and PA0 N-[1-(m-isothiocyanatophenyl)cyclohexyl]isopropylamine.